The present invention relates to an instrument and method for measuring the optical quality of an eye in a human subject. The instrument, which can be of either a single or double pass design and may include three-separate channels, permits real-time, simultaneous measurement of optical aberrations in the eye, retro-illumination of tear film to assess tear film stability, and visual performance. Tear film instability and optical aberrations can affect the optical quality and, consequently, the visual performance of the eye. By monitoring tear film stability and optical aberrations simultaneously in real time with visual performance, an operator may use the present instrument to more accurately assess conditions and diseases of the eye, including dry eye disease (DED) in a human subject.
The International Dry Eye Workshop (DEWS) defined Dry Eye Disease (DED) as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface (DEWS 2007). Irritative symptoms are largely responsible for the public health burden and for the care-seeking behavior of dry eye patients and their desire for therapy. Notably, dry eye patients commonly complain of transiently blurred vision that temporarily clears with a blink (Nichols et al, 1999; Begley et al 2001; Sade de Paiva et al 2003).
The prevalence of dry eye ranges from about 5% to over 35% across large epidemiological studies (DEWS 2007). The large variance in the reported prevalence rates originates from the heterogeneity of the diseases currently classified as DED and the fact that no single diagnostic test can be performed in the clinic to reliably distinguish individuals with DED from those without DED. Instead, a battery of tests are routinely employed which can be broken into symptom questionnaires, grading of ocular surface staining, measures of tear film stability, measures of tear flow, and measures of tear composition. The combination of tests is burdensome for both patients and physicians as these tests currently rely upon physician/patient interaction for reliable collection and interpretation. For example, currently an ophthalmologist may conduct an ocular surface exam which includes tear breakup with fluorescein, surface staining assessment with fuorescein/yellow filter, a Schirmer I test without anesthetic, and lid and meibomian morphology to test for dry eye.
Accordingly, dry eye disease is typically diagnosed in view of the patient's symptoms considered together with the results of the tests ophthalmologists perform (e.g., tear film stability and tear flow). While numerous symptom questionnaires exist with varying degrees of validation, the Ocular Surface Disease Index (OSDI) is the most widely utilized. Tear film stability is commonly measured by determining the Tear Film Break-Up Time (TFBUT). A standard volume of fluorescein dye is applied to the eye, the patient is allowed to blink and the time between the blink and the first appearance of a dark spot is recorded as the tear break-up time. Reflex tear flow is measured using the Schirmer test. It is accepted that the wide intrasubject variation on these tests is influenced by both day-to-day and visit to-to-visit fluctuation. It must also be recognized that there is wide intrasubject variation with regard to the impact of tear film stability between blinks (i.e., some patients may experience tear film break-up before their next blink). This source of variability is often used to explain why some dry eye disease patients complain of “transiently” blurred vision. To eliminate between blink variability across tests, tear film break-up must be measured both objectively and subjectively at the same time. Unfortunately, no standard instrument exists which can simultaneously measure tear break-up both objectively and subjectively.
Consistent with clinical practice, the DEWS sub-committee on clinical trial design recommended that the following endpoints be included in clinical drug trials: 1) An objective measure of visual function (e.g., Functional Visual Acuity); 2) Determination of tear volume and production (e.g., Schirmer test or fuorescein dilution test); 3) Determination of tear stability (e.g., tear breakup with fuorescein or a non-invasive tear breakup device such as videokeratography); 4) Measurement of tear composition (e.g., osmolarity, determination of specific protein content, or the measurement of inflammatory mediators in tears); and 5) Measurement of ocular surface integrity.
Of these suggested measures the need for an objective and reliable measure of visual function has yet to be satisfied. Three requirements should be met to optimally and non-invasively measure the relationship between tear stability, aberrations, and functional outcomes: 1) measurements should be performed without anesthesia, pupil dilation or the instillation of dyes (e.g., fluorescein) (see Koh et al, 2008); 2) visual testing for tear film irregularities is time sensitive and stimuli should be presented relative to a patient's blink; and 3) all measurements should be performed simultaneously using a stimulus which is optimally sensitive to tear film induced aberrations (see Liu et al, 2010).
Recognizing the difficulty of measuring visual function within a blink interval the scientific advancement has instead focused upon the real time measurement of optical aberrations as a surrogate for functional loss. Indeed, several studies have confirmed that tear film stability impacts ocular aberrations (Thibos and Hong, 1999; Tutt et al, 2000; Koh et al, 2002; Koh et al, 2008; Montés-Micó et al, 2004; Montés-Micó et al, 2005) using a variety of measurement techniques (e.g., double-pass optical method (Albarran et al, 1997; Montés-Micó et al, 2005; Diaz-Douton et al, 2006), Hartmann-Shack aberrometer (Montés-Micó et al, 2004; Thibos and Hong, 1999; Koh et al, 2002; Diaz-Douton et al, 2006; Koh et al, 2008), contrast sensitivity and vessel contrast measurements (Tutt et al 2000), retro-illumination of the tear film (Liu et al, 2010), videokeratography (Goto et al, 2002), and the Pentacam with fluorescein (Zhuang et al, 2010).
While these surrogate markers for functional loss have shown sensitivity and specificity to dry eye disease, their inability to simultaneously measure tear break-up both objectively and subjectively means that the clinical significance of their findings is hard to quantify. For example, the Objective Scatter Index (OSI) from the Optical Quality Analysis System (OQAS™) (Visiometrics S. L., Ctra. N-150 Km 14.5, Mòdul TR20-IPCT E-08227 Terrassa, Spain) evaluates the amount of light in the outside of a double-pass image in relation to the amount of light in the centre of a double-pass image. The higher the OSI value, the greater the scatter. Without an understanding of how an observed OSI value relates to functional performance (e.g., visual acuity) this represents an arbitrary measure of optical quality which cannot be translated into an endpoint which is clinically meaningful to either physicians or patients.
Consequently, there is a need for instruments and diagnostic methods that can more accurately measure, in real time, optical aberrations in the eye of a patient and their functional consequences. This will allow physicians to interpret the impact of the particular optical aberrations a patient is experiencing in his or her eye in terms of their functional consequences for that patient and can then help guide the physician's choice of an appropriate level of treatment.
The present invention satisfies this need by providing instrumentation and protocols for simultaneously evaluating the relationship between metrics of optical quality in the eye of a patient obtained from double pass images, psychophysical measures of visual performance, and a retro-illumination image of the tear film. The addition of the retro-illumination image in the present instrument enables one to not only map the location of a tear break-up (e.g., central versus peripheral) in a patient's eye, but to also correlate the location of a tear break-up with any changes in optical quality and visual performance. By providing simultaneous measurement of these parameters in real-time, the present instrument reduces or eliminates variability, which can occur when measurements are taken between eye blinks or at separate points in time. Accordingly, the present instrument enables the operator to assess a patient's visual quality more accurately than previously possible.